PF1022 substance is a known cyclodepsipeptide which was discovered as a result of studies on anthelmintic substances against fowl roundworms [refer to Japanese patent application Kokai No. Hei 3-35796, European patent application publication No. 0382173A2 and J. Antibiotics, 45, 692, (1992)]. The PF1022substance is a fermentation product which is produced by the cultivation of a filamentous fungus, PF1022 strain (deposited under FERM BP-2671 with National Institute of Bioscience and Human-Technology Agency in Tsukuba-City in terms of the Budapest Treaty) belonging to Agonomycetales. PF1022 substance is a compound classified into a class of cyclodepsipeptide compounds represented by the following formula (A) ##STR2##
wherein Me stands for methyl group.
The cyclodepsipeptide represented by the above formula (A) includes the following eight particular substances.
PF1022 substance: R.sup.1.dbd.R.sup.3.dbd.Me, R.sup.2.dbd.R.sup.4.dbd.CH.sub.2 C.sub.6 H.sub.5 PA1 PF1022 B substance: R.sup.1.dbd.R.sup.2.dbd.R.sup.3.dbd.R.sup.4.dbd.CH.sub.2 C.sub.6 H.sub.5 PA1 PF1022 C substance: R.sup.1.dbd.Me, R.sup.2.dbd.R.sup.3.dbd.R.sup.4.dbd.CH.sub.2 C.sub.6 H.sub.5 PA1 PF1022 D substance: R.sup.1.dbd.R.sup.3.dbd.R.sup.4.dbd.Me, R.sup.2.dbd.CH.sub.2 C.sub.6 H.sub.5 PA1 PF1022 E substance: R.sup.1.dbd.R.sup.3.dbd.Me, R.sup.2.dbd.CH.sub.2 C.sub.6 H.sub.4 OH-p, R.sup.4.dbd.CH.sub.2 C.sub.6 H.sub.5 PA1 PF1022 F substance: R.sup.1.dbd.R.sup.2.dbd.R.sup.3.dbd.R.sup.4.dbd.Me PA1 PF1022 G substance: R.sup.1.dbd.R.sup.2.dbd.R.sup.3.dbd.Me, R.sup.4.dbd.CH.sub.2 C.sub.6 H.sub.4 OH-p PA1 PF1022 H substance: R.sup.1.dbd.R.sup.3.dbd.Me, R.sup.2.dbd.R.sup.4.dbd.CH.sub.2 C.sub.6 H.sub.4 OH-p
The PF1022 substance is a cyclodepsipeptide which is formed of L--N-methylleucine [(CH.sub.3).sub.2 CHCH.sub.2 CH(NHCH.sub.3)COOH] (abbreviated as H--L-MeLeu-OH), D-lactic acid [CH.sub.3 CH(OH)--COOH] (abbreviated as H--D-Lac-OH) and D-phenyl-lactic acid [C.sub.6 H.sub.5 CH.sub.2 CH(OH)COOH] (abbreviated H--D-PhLac-OH) via ester-bonds and amido-bonds and which may also be represented by the following formula (B):
Formula B: Cyclo(L-MeLeu-D-Lac-L-MeLeu-D-PhLac-L-MeLeu-D-Lac-L-MeLeu-D-PhLac)
The cultivation of the filamentous fungus PF1022 strain results not only in the production of PF1022 substance as the main product, but also in the production of PF1022 B substance, PF1022 C substance, PF1022 D substance, PF1022 E substance, PF1022 F substance, PF1022 G substance and PF1022 H substance which have the structures represented in the above formula (A), respectively [see Japanese patent application first publications Kokai Nos. Hei 3-35796, 5-170749 and 6-184126 and Japanese patent application No. Hei 8-208201 (filed on Aug. 7, 1996, not yet laid open)].
The PF1022 substance and PF1022 B to H substances all possess anthelmintic activities and have specific structural characteristics such that they have a common cyclodepsipeptide structure as a basic skeleton, that they have, as side chains, four N-methyl groups, four isobutyl groups, 0-4 methyl groups, 0-4 benzyl groups and 0-2 p-hydroxybenzyl groups and also that they have eight asymmetric carbon atoms in their molecules. Further, it can be presumed that the presence of a 24-membered ring formed of the four ester-linkages and four amido-linkages as shown in the formula (A) above plays an important role in the expression of biological activities.
So-called helminthic infections can cause serious damages to human and animal health and also to agricultural and stock-breeding industries, so that there always exists in the art, as an important theme, a demand for finding and providing such novel and useful substances which exhibit anthelmintic activities.
As explained above, PF1022 substance was found originally as a fermentation product, and later was prepared by chemical syntheses [see Japanese patent application first publication Kokai No. Hei 5-320148, and Biosci. Biotech. Biochem., 58, 1193 (1994)].
It is already known that PF1022 substance and PF1022 B to H substances themselves possess very high anthelmintic activities, but some researcher groups are still working in an attempt to produce and find out novel related substance(s) having a higher anthelmintic activity, with utilizing those PF1022 substances as the starting materials.
We, the present inventors, also have proceeded investigations from the initial stage when PF1022 substance was found, in order to produce and find out novel derivatives with starting from PF1022 substance and PF1022 B to H substances, and we have already found several novel derivatives (see internationally published specification No. WO94/19334 of PCT application No. PCT/JP/00252 and European patent application publication No. 0685469 A1 and Japanese patent application No. Hei 7-244051). One of the other researcher groups also has disclosed some novel derivatives as produced by total synthetic processes (see PCT international publications WO093/19033 and No. WO95/07272).